Novel Compound Heterozygous Mutations in NLRP1 Are Potential Causes of Aberrant Inflammation Presented as a Chronic Urticarial Rash

The immune system plays a vital role against microbes and pathogens that threaten our health. As part of host defense, innate immune receptors, known as pattern recognition receptors (PRRs), sense different pathogen-associated molecular patterns (PAMPS) and Danger-associated molecular patterns (DAMPS), and initiate inflammation. Some PRRs trigger inflammation through a complex structure called the inflammasome. Several mutations in these receptors have been linked to different autoimmune and autoinflammatory disorders with variable clinical phenotypes. For example, patients with heterozygous gain of function mutations in the pyrin domain of NACHT, LRR, and PYD domains-containing protein 1 (NLRP1) present with multiple self-healing palmoplantar carcinoma ( MSPC) and dyskeratosis, but in a separate report, patients with biallelic mutations in the linker region of NLRP1 have an autoinflammatory disease with periodic fevers, arthritis, and dyskeratosis. In this paper, whole-genome sequencing detected novel compound heterozygous mutations in the seventh Leucine-rich repeat (LRR) domain and the “function-to-find” domain (FIIND) of NLRP1 in a patient presenting with a chronic urticarial rash. Sanger sequencing confirmed the mutations, and western blot revealed that NLRP1 protein is present in the patient and parents’ samples to a similar level as the healthy donor control. RNA sequencing identified differentially expressed genes in the patient compared to her healthy parents. The pathways in which these differentially expressed genes are involved have been studied as well to understand their connection with urticaria rash. This study presents new compound heterozygous mutations in different domains of NLRP1, which will facilitate a better understanding of the functions of these domains and their correlation with clinical phenotypes of the disease.